Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
The EpiDRIVE study aims to identify cfDNA-based epigenetic determinants of response in metastatic colorectal cancer (mCRC) patients treated with EGFR- or VEGF-targeted therapy.
By integrating 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiling, this study seeks to develop a predictive biomarker panel capable of differentiating responders from non-responders to targeted therapy.
Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related death. Although targeted agents such as anti-EGFR (cetuximab, panitumumab) and anti-VEGF (bevacizumab) therapies have improved survival, treatment response varies widely even among molecularly defined subgroups.
Traditional biomarkers, including RAS/BRAF mutation and tumor sidedness, fail to accurately predict therapeutic efficacy.
Recent studies highlight the potential of cell-free DNA (cfDNA) methylation (5mC) and hydroxymethylation (5hmC) as sensitive, non-invasive indicators of tumor biology and treatment dynamics.
The EpiDRIVE study integrates cfDNA 5mC/5hmC sequencing and targeted validation to discover and verify epigenetic determinants of therapeutic response.
Discovery phase: Whole-genome 5mC/5hmC profiling to identify differentially modified regions between responders and non-responders.
Training phase: Targeted sequencing to establish a predictive cfDNA epigenetic panel (EpiDRIVE panel).
Validation phase: qPCR-based validation of selected markers in an independent cohort to confirm predictive accuracy.
This study aims to provide a non-invasive biomarker framework to predict and monitor efficacy of EGFR- and VEGF-targeted therapies in mCRC, ultimately guiding personalized treatment selection.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Discovery Cohort - Long PFS Group (Responder) | Patients with metastatic colorectal cancer (mCRC) who received EGFR- or VEGF-targeted therapy and achieved a progression-free survival (PFS) ≥ 12 months, classified as clinical responders. Pre-treatment plasma cfDNA samples were analyzed by genome-wide 5mC/5hmC sequencing to identify epigenetic determinants associated with durable treatment response. |
| |
| Discovery Cohort - Short PFS Group (Non-Responder) | Patients with mCRC who received EGFR- or VEGF-targeted therapy and showed progression-free survival (PFS) < 12 months, classified as non-responders. Pre-treatment cfDNA samples were analyzed using genome-wide 5mC/5hmC sequencing and compared with long-PFS responders to identify differential methylation and hydroxymethylation patterns associated with resistance. |
| |
| Training Cohort - Long PFS Group (Responder) | Independent mCRC cohort with PFS ≥ 12 months following EGFR- or VEGF-targeted therapy. Candidate cfDNA 5mC/5hmC markers identified in the discovery phase were validated using targeted sequencing (EpiDRIVE assay) to construct the predictive epigenetic biomarker panel. |
| |
| Training Cohort - Short PFS Group (Non-Responder) | Independent mCRC patients with PFS < 12 months after targeted therapy. Targeted sequencing using the EpiDRIVE assay was conducted to refine and optimize the predictive model by comparing short- vs long-PFS cases. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| cfDNA 5mC/5hmC Sequencing (EpiDRIVE Discovery Phase) | Diagnostic Test | High-throughput genome-wide sequencing of cfDNA methylation (5mC) and hydroxymethylation (5hmC) profiles from pre-treatment plasma samples in the discovery cohort to identify epigenetic determinants of targeted-therapy response (PFS ≥ 12 months vs < 12 months). |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-Free Survival (PFS) according to cfDNA 5mC/5hmC biomarker profile | Progression-free survival (PFS) among patients with metastatic colorectal cancer (mCRC) receiving EGFR- or VEGF-targeted therapy, stratified by cfDNA 5mC/5hmC-based biomarker status. | Up to 36 months from therapy initiation |
| Measure | Description | Time Frame |
|---|---|---|
| Overall Survival (OS) | Time from initiation of EGFR- or VEGF-targeted therapy to death from any cause. Overall survival will be analyzed in relation to cfDNA 5mC/5hmC biomarker-defined groups (high vs low EpiDRIVE score) to assess whether epigenetic cfDNA profiles are associated with differences in survival outcomes. | Up to 60 months from therapy initiation |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Patients diagnosed with Stage IV colorectal adenocarcinoma who received EGFR-targeted or VEGF-targeted therapy and had available pre-treatment plasma samples for cfDNA analysis.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Ajay Goel, PhD | Contact | 626-359-8111 | ajgoel@coh.org |
| Name | Affiliation | Role |
|---|---|---|
| Ajay Goel, PhD | City of Hope Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| City of Hope Medical Center | Recruiting | Duarte | California | 91016 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39820673 | Background | Xu C, Mannucci A, Esposito F, Oliveres H, Alonso-Orduna V, Yubero A, Fernandez-Martos C, Salud A, Gallego J, Martin-Richard M, Fernandez-Plana J, Guillot M, Aparicio J, Fakih M, Kopetz S, Feliu J, Maurel J, Goel A. An Exosome-Based Liquid Biopsy Predicts Depth of Response and Survival Outcomes to Cetuximab and Panitumumab in Metastatic Colorectal Cancer: The EXONERATE Study. Clin Cancer Res. 2025 Mar 17;31(6):1002-1015. doi: 10.1158/1078-0432.CCR-24-1934. | |
| 36656585 |
Not provided
Not provided
Data collected for the study will be made available to others, including de-identified participant data, at publication, via a signed data access agreement and at the discretion of the investigators' approval of the proposed use of such data
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
| Validation Cohort - Long PFS Group (Responder) | Separate validation cohort of mCRC patients achieving PFS ≥ 12 months under EGFR- or VEGF-targeted therapy. qPCR-based EpiDRIVE assay was used to confirm predictive accuracy of the cfDNA 5mC/5hmC biomarker panel in identifying durable responders. |
|
| Validation Cohort - Short PFS Group (Non-Responder) | Independent validation cohort of mCRC patients with PFS < 12 months after targeted therapy. cfDNA was analyzed using the qPCR-based EpiDRIVE assay to assess model specificity and distinguish non-responders from long-term responders. |
|
|
| EpiDRIVE Assay (Targeted Sequencing / qPCR Validation) | Diagnostic Test | Targeted sequencing or qPCR-based validation of cfDNA 5mC/5hmC markers identified from the discovery phase to develop and validate a predictive biomarker model discriminating patients with long vs short progression-free survival after EGFR-/VEGF-targeted therapy. |
|
| Background |
| Koroukian SM, Booker BD, Vu L, Schumacher FR, Rose J, Cooper GS, Selfridge JE, Markt SC. Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer. JAMA Netw Open. 2023 Jan 3;6(1):e2250030. doi: 10.1001/jamanetworkopen.2022.50030. |
| 37538108 | Background | Tirendi S, Marengo B, Domenicotti C, Bassi AM, Almonti V, Vernazza S. Colorectal cancer and therapy response: a focus on the main mechanisms involved. Front Oncol. 2023 Jul 19;13:1208140. doi: 10.3389/fonc.2023.1208140. eCollection 2023. |
| 32296018 | Background | Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther. 2020 Mar 20;5(1):22. doi: 10.1038/s41392-020-0116-z. |
| 33508734 | Background | Cai Z, Zhang J, He Y, Xia L, Dong X, Chen G, Zhou Y, Hu X, Zhong S, Wang Y, Chen H, Xie D, Liu X, Liu J. Liquid biopsy by combining 5-hydroxymethylcytosine signatures of plasma cell-free DNA and protein biomarkers for diagnosis and prognosis of hepatocellular carcinoma. ESMO Open. 2021 Feb;6(1):100021. doi: 10.1016/j.esmoop.2020.100021. Epub 2021 Jan 25. |
| 30922396 | Background | Zeng C, Stroup EK, Zhang Z, Chiu BC, Zhang W. Towards precision medicine: advances in 5-hydroxymethylcytosine cancer biomarker discovery in liquid biopsy. Cancer Commun (Lond). 2019 Mar 29;39(1):12. doi: 10.1186/s40880-019-0356-x. |
| 39393034 | Background | West-Szymanski DC, Zhang Z, Cui XL, Kowitwanich K, Gao L, Deng Z, Dougherty U, Williams C, Merkle S, He C, Zhang W, Bissonnette M. 5-Hydroxymethylated Biomarkers in Cell-Free DNA Predict Occult Colorectal Cancer up to 36 Months Before Diagnosis in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. JCO Precis Oncol. 2024 Oct;8:e2400277. doi: 10.1200/PO.24.00277. Epub 2024 Oct 11. |
| 38464122 | Background | West-Szymanski DC, Zhang Z, Cui XL, Kowitwanich K, Gao L, Deng Z, Dougherty U, Williams C, Merkle S, Moore M, He C, Bissonnette M, Zhang W. Machine learning identifies cell-free DNA 5-hydroxymethylation biomarkers that detect occult colorectal cancer in PLCO Screening Trial subjects. bioRxiv [Preprint]. 2024 Feb 26:2024.02.25.581955. doi: 10.1101/2024.02.25.581955. |
| 39817679 | Background | Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025 Jan-Feb;75(1):10-45. doi: 10.3322/caac.21871. Epub 2025 Jan 16. |
| 40055844 | Background | Song D, Zhang Z, Zheng J, Zhang W, Cai J. 5-Hydroxymethylcytosine modifications in circulating cell-free DNA: frontiers of cancer detection, monitoring, and prognostic evaluation. Biomark Res. 2025 Mar 7;13(1):39. doi: 10.1186/s40364-025-00751-9. |
| 40375296 | Background | Baldassarre G, L de la Serna I, Vallette FM. Death-ision: the link between cellular resilience and cancer resistance to treatments. Mol Cancer. 2025 May 15;24(1):144. doi: 10.1186/s12943-025-02339-1. |
| 33930176 | Background | Ferrara R, Imbimbo M, Malouf R, Paget-Bailly S, Calais F, Marchal C, Westeel V. Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer. Cochrane Database Syst Rev. 2021 Apr 30;4(4):CD013257. doi: 10.1002/14651858.CD013257.pub3. |
| 38212123 | Background | Guler GD, Ning Y, Coruh C, Mognol GP, Phillips T, Nabiyouni M, Hazen K, Scott A, Volkmuth W, Levy S. Plasma cell-free DNA hydroxymethylation profiling reveals anti-PD-1 treatment response and resistance biology in non-small cell lung cancer. J Immunother Cancer. 2024 Jan 11;12(1):e008028. doi: 10.1136/jitc-2023-008028. |
| 38667328 | Background | Shao J, Xu Y, Olsen RJ, Kasparian S, Sun K, Mathur S, Zhang J, He C, Chen SH, Bernicker EH, Li Z. 5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer. Cells. 2024 Apr 19;13(8):715. doi: 10.3390/cells13080715. |
| 37904926 | Background | Li Q, Huang CC, Huang S, Tian Y, Huang J, Bitaraf A, Dong X, Nevalanen MT, Patel M, Wong J, Zhang J, Manley BJ, Park JY, Kohli M, Gore EM, Kilari D, Wang L. 5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapies. medRxiv [Preprint]. 2024 Oct 17:2023.10.13.23296758. doi: 10.1101/2023.10.13.23296758. |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
Not provided
Not provided